EP0925284B1 - New polycyclic phthalazin derivatives and their use - Google Patents

New polycyclic phthalazin derivatives and their use Download PDF

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EP0925284B1
EP0925284B1 EP97931802A EP97931802A EP0925284B1 EP 0925284 B1 EP0925284 B1 EP 0925284B1 EP 97931802 A EP97931802 A EP 97931802A EP 97931802 A EP97931802 A EP 97931802A EP 0925284 B1 EP0925284 B1 EP 0925284B1
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alkyl
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EP0925284A1 (en
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Lothar Heinisch
Ute Möllmann
Wolfgang Witte
Christiane Cuny
Ernst Roemer
Walter Werner
Udo Gräfe
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Gruenenthal GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

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  • the invention relates to new polycyclic phthalazine derivatives, especially 2-carboxyalkyl and 2-carboxyaryl-substituted Maduraphthalazines (10,12,15,16-tetrahydroxy-8-methoxy-11-methyl-1,9,14-trioxo-1,2,6,7,9,14-hexahydronaphtaceno- [1,2-g] - phthalazines) and their salts, esters and amides. They are highly antibacterial, in particular against gram-positive, especially against multi-resistant Staphylococci (MRSA) and resistant enterococci, effective Substances used to fight infectious diseases can be used in humans and animals.
  • MRSA multi-resistant Staphylococci
  • the Connections are widely used for making pharmaceutical preparations and application forms.
  • the compounds are the first representatives of a previously unknown ring system, naphthaceno [1,2-g] phthalazine. They are derived from madura hydroxylactone or maduranic acid, which can be obtained biotechnologically from Actinomadura rubra (W. Fleck, DG Strauss, J. Meyer, Z. Allg. Mikrobiol. 18 , 368 - 398 (1978)).
  • the structure of Madurahyroxylactone (Formula II) was elucidated by Paul and co-workers (EF Paulus, K. Dornberger, W. Werner, D. Fenske, Acta Cryst. (1994) C50, 2064 - 2067). Madura hydroxyl lactone itself has insufficient biological activity.
  • Madura hydroxylactone belongs to the class of benzonaphthacene quinones, among which the benanomycins and pradimycins in particular have recently become known as interesting antifungal substances (T. Oki in "Recent Progress in Antifungal Chemotherapy", Eds. H. Yamaguchi, GS Kobayachi, H. Takahashi , Marcel Dekker, Inc., New York, Basel, Hong Kong, 1992, p. 38).
  • Another antibiotic compound with the designation LL-D 42067 ⁇ , also based on a ring system, is known from US 4,859,598.
  • the compound is biotechnologically obtainable from a subspecies of Actinomadura madurae and has an antibacterial and anti- parasitic effect. The antibacterial activity against different type strains is described. However, it is not known that the compound is sufficiently effective against current problem germs such as multi-resistant staphylococci or vancomycin-resistant strains.
  • the invention serves to provide 2-substituted, especially 2-carboxyalkyl and 2-carboxyaryl-substituted maduraphthalazines (10,12,15,16-tetrahydroxy-8-methoxy-11-methyl-1,9,14-trioxo-1 , 2,6,7,9,14-hexahydronaphthaceno [1,2-g] phthalazines) and corresponding salts, esters and amides and their use.
  • the aim of the compounds is to broaden the range of antibacterial preparations which are active especially against gram-positive bacteria, especially against multi-resistant staphylococci. To solve this problem, the new compounds are advantageous because the previously known antibiotics or anti-infectives have major disadvantages, such as. B.
  • R 1 carboxyalkyl or carboxyaryl and R 2 and R 3 independently represent hydrogen or acyl, and salts, esters and amides of compounds of formula I, with the proviso that R 1 is substituted or unsubstituted carboxyphenyl, wherein the substituents the group comprising OH, Oalkyl, OAryl, halogen, alkyl and aryl is selected, is different if R 3 is C 1-8 alkanoyl.
  • alkyl also in word combinations such as alkoxy or carboxyalkyl
  • alkoxy or carboxyalkyl means C 1-10 -alkyl, straight-chain or branched-chain, preferably C 1-4 -alkyl, while under an aryl residue (also one of the aryl residues mentioned below or in word combinations such as Aralkyl) substituted or unsubstituted aryl, in particular corresponding phenyl, the substituents of which can be OH, Oalkyl, OAryl, halogen, alkyl, aryl.
  • acyl is primarily C 1-8 alkanoyl, C 1-8 alkoxycarbonyl, aroyl, in particular benzoyl or substituted benzoyl (in which the substituents are the same as in substituted aryl), and optionally by one or two C. 1-4 alkyl radicals substituted carbamoyl.
  • R 1 is carboxy-C 1-4 -alkyl or C 1-4 alkoxycarbonyl-C 1-4 -alkyl or carboxyphenyl
  • R 2 and R 3 are hydrogen, in which the carboxy group in is in free form or in salt form.
  • the compounds of the invention are, for. B. prepared by madura hydroxylactone or maduranic acid (3,9,11,14,15-pentahydroxy-10-methyl-7-methoxy-1,8,13-trioxo-1,3,5,6,8,13- hexahydro-naphthaceno [1,2-f] benzoisofuran) of the formula II with hydrazinoalkylcarboxylic acids or hydrazinophenylcarboxylic acids or their esters and amides, optionally in the form of their salts.
  • the reaction is carried out using suitable solvents, e.g. B. glacial acetic acid.
  • the reaction temperature is usually the boiling point of the solvent, and the reaction time can be up to a few hours.
  • This reaction step is carried out by customary methods of acylating phenolic OH groups, e.g. B. by means of acid anhydride (z. B. Acetic anhydride or propionic anhydride) or by means of chloroformic esters (z. B. Methyl chloroformate) in an alkaline solution, for. B. in 2M sodium hydroxide solution or in tetrahydrofuran / triethylamine.
  • the reaction temperature can be from -20 ° C to + 20 ° C.
  • R 7 is an alkali metal ion (for example Na, K) or an ammonium ion (NH 4 , a mono-, di- or Trialkylammonium ion, e.g. a triethylammonium ion or an N-methyl-D-glucammonium ion).
  • the synthesized compounds can be purified by means of customary methods (for example by recrystallization or column chromatography).
  • the connections provided according to the invention the growth of bacteria, especially gram-positive Bacteria, especially from multi-resistant staphylococci as well as enterococci.
  • bacteria especially gram-positive Bacteria, especially from multi-resistant staphylococci as well as enterococci.
  • the compounds are also resistant to quinolones Staphylococci as well as against multi-resistant, also against glycopeptide resistant, e.g. B. against vancomycin resistant Hospital strains (MRSA) are highly effective.
  • results of the antibacterial testing are in the Table summarized. The results show that the substances shown according to the invention against some strains of the inhibitors of the comparison substances significantly outperform and successful bacterial Can overcome resistance.
  • the compounds of general formula I are suitable due to their antibacterial properties as a medicine for bacterial infections, in particular in infections with multi-resistant staphylococci.
  • the connections of formula I either alone or with physiologically compatible Auxiliaries or carriers are used, in principle all the usual pharmacological application forms and physiologically acceptable dosages possible are.
  • the application takes place e.g. B. orally or parenterally, such as B. intravenously.
  • Substance 3 can be added, for example, by adding an amine Triethylamine or N-methyl-D-glucamine, all in one suitable solvents, for example tetrahydrofuran, a water soluble trialkylammonium salt, for example a triethylammonium salt or an N-methyl-D-glucammonium salt, be won.
  • suitable solvents for example tetrahydrofuran
  • a water soluble trialkylammonium salt for example a triethylammonium salt or an N-methyl-D-glucammonium salt

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Abstract

PCT No. PCT/FI96/03632 Sec. 371 Date Jan. 28, 2000 Sec. 102(e) Date Jan. 28, 2000 PCT Filed Jul. 9, 1997 PCT Pub. No. WO98/07706 PCT Pub. Date Feb. 26, 1998Polycyclic phthalazines, in particular 2-substituted maduraphthalazines (10,12,15,16-tetrahydroxy-8-methoxy-11-methyl-1,9,14-trioxo-1,2,6,7,9,14-hexahydronaphthaceno-1,2-g-phthalazines), of formula I and their use against gram-positive bacterial strains, particularly against multi-resistant staphylococci (MRSA) and against glycopeptide-resistant, for example vancomycin-resistant, enterococci. The polycyclic phthalazines are thus suitable for preparing anti-bacterially effective pharmaceutical compositions. In formula I, R1 is carboxyalkyl or carboxyaryl, and R2 and R3 represent H or acyl (for example CO-alkyl or COO-alkyl), with R1 being different from optionally substituted carboxyphenyl when R3 represents C1-8 alkanoyl. The invention also relates to salts, amides and esters of compounds of formula I.

Description

Die Erfindung betrifft neue polycyclische Phthalazinderivate, speziell 2-carboxyalkyl- und 2-carboxyaryl-substituierte Maduraphthalazine (10,12,15,16-Tetrahydroxy-8-methoxy-11-methyl-1,9,14-trioxo-1,2,6,7,9,14-hexahydronaphtaceno-[1,2-g]-phthalazine) sowie deren Salze, Ester und Amide. Sie stellen stark antibakterielle, insbesondere gegen grampositive, speziell gegen multiresistente Staphylokokken (MRSA) und resistente Enterokokken, wirksame Substanzen dar, die zur Bekämpfung von Infektionskrankheiten bei Menschen und Tieren verwendbar sind. Die Verbindungen sind für die Herstellung verschiedenster pharmazeutischer Zubereitungen und Applikationsformen geeignet.The invention relates to new polycyclic phthalazine derivatives, especially 2-carboxyalkyl and 2-carboxyaryl-substituted Maduraphthalazines (10,12,15,16-tetrahydroxy-8-methoxy-11-methyl-1,9,14-trioxo-1,2,6,7,9,14-hexahydronaphtaceno- [1,2-g] - phthalazines) and their salts, esters and amides. They are highly antibacterial, in particular against gram-positive, especially against multi-resistant Staphylococci (MRSA) and resistant enterococci, effective Substances used to fight infectious diseases can be used in humans and animals. The Connections are widely used for making pharmaceutical preparations and application forms.

Die Verbindungen sind erste Vertreter eines bisher unbekannten Ringsystems, des Naphthaceno-[1,2-g]-phthalazins. Sie leiten sich von Madurahydroxylakton bzw. Maduransäure ab, welches aus Actinomadura rubra biotechnologisch gewinnbar ist (W. Fleck, D. G. Strauss, J. Meyer, Z. Allg. Mikrobiol. 18, 368 - 398 (1978)). Die Struktur des Madurahyroxylaktons (Formel II) wurde von Paulus und Mitarbeitern aufgeklärt (E. F. Paulus, K. Dornberger, W. Werner, D. Fenske, Acta Cryst. (1994) C50, 2064 - 2067). Madurahydroxylakton selbst besitzt nur ungenügende biologische Wirksamkeit. Madurahydroxylakton gehört zu der Klasse der Benzonaphthacenchinone, unter denen in letzter Zeit insbesondere die Benanomycine und Pradimycine als interessante antifungale Substanzen bekannt geworden sind (T. Oki in "Recent Prögress in Antifungal Chemotherapy", Eds. H. Yamaguchi, G. S. Kobayachi, H. Takahashi, Marcel Dekker, Inc., New York, Basel, Hong Kong, 1992, S. 38).The compounds are the first representatives of a previously unknown ring system, naphthaceno [1,2-g] phthalazine. They are derived from madura hydroxylactone or maduranic acid, which can be obtained biotechnologically from Actinomadura rubra (W. Fleck, DG Strauss, J. Meyer, Z. Allg. Mikrobiol. 18 , 368 - 398 (1978)). The structure of Madurahyroxylactone (Formula II) was elucidated by Paul and co-workers (EF Paulus, K. Dornberger, W. Werner, D. Fenske, Acta Cryst. (1994) C50, 2064 - 2067). Madura hydroxyl lactone itself has insufficient biological activity. Madura hydroxylactone belongs to the class of benzonaphthacene quinones, among which the benanomycins and pradimycins in particular have recently become known as interesting antifungal substances (T. Oki in "Recent Progress in Antifungal Chemotherapy", Eds. H. Yamaguchi, GS Kobayachi, H. Takahashi , Marcel Dekker, Inc., New York, Basel, Hong Kong, 1992, p. 38).

Eine weitere antibiotische Verbindung mit der Bezeichnung LL-D 42067β, ebenfalls basierend auf einem Ringsystem, ist aus US 4,859,598 bekannt. Die Verbindung ist biotechnologisch aus einer Subspezies von Actinomadura madurae gewinnbar und antibakteriell und antiparasitär wirksam. Die antibakterielle Wirksamkeit gegenüber verschiedenen Typenstämmen ist beschrieben. Eine ausreichende Wirksamkeit der Verbindung gegenüber aktuellen Problemkeimen wie multiresistenten Staphylokokken oder vancomycinresistenten Stämmen ist jedoch nicht bekannt.Another antibiotic compound with the designation LL-D 42067β, also based on a ring system, is known from US 4,859,598. The compound is biotechnologically obtainable from a subspecies of Actinomadura madurae and has an antibacterial and anti- parasitic effect. The antibacterial activity against different type strains is described. However, it is not known that the compound is sufficiently effective against current problem germs such as multi-resistant staphylococci or vancomycin-resistant strains.

Die Erfindung dient zur Bereitstellung von 2-substituierten, speziell 2-carboxyalkyl- und 2-carboxyaryl-substituierten Maduraphthalazinen (10,12,15,16-Tetrahydroxy-8-methoxy-11-methyl-1,9,14-trioxo-1,2,6,7,9,14-hexahydronaphthaceno-[1,2-g]-phthalazinen) und entsprechenden Salzen, Estern und Amiden sowie zu ihrer Verwendung. Mit den Verbindungen wird angestrebt, die Palette antibakterieller, speziell gegen grampositive Bakterien, besonders gegen multiresistente Staphylokokken wirksamer Präparate zu vergrößern. Für die Lösung dieser Aufgabe sind die neuen Verbindungen deshalb von Vorteil, weil die bisher bekannten Antibiotika bzw. Antiinfektiva große Nachteile, wie z. B. ungenügende Wirksamkeit gegenüber resistenten Bakterienstämmen, aufweisen (W. Witte, C. Braulke, D. Heuck, C. Cuny; "Analysis of nosocomial outbreaks with multiply and methicillin resistent staphylococcus aureus (MRSA) in Germany: implications for hospital hygiene", Infection 22, (1994), Suppl. 2, 128 - 134; G. M. Eliopulos, "Increasing problems in the therapy of enterococcal infection", Eur. J. Clin. microbiol. Infect. Dis. 12, (1993) 409 - 412.The invention serves to provide 2-substituted, especially 2-carboxyalkyl and 2-carboxyaryl-substituted maduraphthalazines (10,12,15,16-tetrahydroxy-8-methoxy-11-methyl-1,9,14-trioxo-1 , 2,6,7,9,14-hexahydronaphthaceno [1,2-g] phthalazines) and corresponding salts, esters and amides and their use. The aim of the compounds is to broaden the range of antibacterial preparations which are active especially against gram-positive bacteria, especially against multi-resistant staphylococci. To solve this problem, the new compounds are advantageous because the previously known antibiotics or anti-infectives have major disadvantages, such as. B. insufficient activity against resistant bacterial strains (W. Witte, C. Braulke, D. Heuck, C. Cuny; "Analysis of nosocomial outbreaks with multiply and methicillin resistant staphylococcus aureus (MRSA) in Germany: implications for hospital hygiene", Infection 22 , (1994), Suppl. 2, 128-134; GM Eliopulos, "Increasing problems in the therapy of enterococcal infection", Eur. J. Clin. Microbiol. Infect. Dis. 12 , (1993) 409-412.

Die Aufgabe wird erfindungsgemäß gelöst durch die Bereitstellung von neuen polycyclischen Phthalazinen der Formel I

Figure 00040001
worin R1 = Carboxyalkyl oder Carboxyaryl bedeutet und R2 und R3 unabhängig voneinander für Wasserstoff oder Acyl stehen, sowie Salze, Ester und Amide von Verbindungen der Formel I, mit der Maßgabe, daß R1 von gegebenenfalls substituiertem Carboxyphenyl, worin die Substituenten aus der OH, OAlkyl, OAryl, Halogen, Alkyl und Aryl umfassenden Gruppe ausgewählt sind, verschieden ist, wenn R3 C1-8-Alkanoyl bedeutet.The object is achieved according to the invention by providing new polycyclic phthalazines of the formula I.
Figure 00040001
wherein R 1 = carboxyalkyl or carboxyaryl and R 2 and R 3 independently represent hydrogen or acyl, and salts, esters and amides of compounds of formula I, with the proviso that R 1 is substituted or unsubstituted carboxyphenyl, wherein the substituents the group comprising OH, Oalkyl, OAryl, halogen, alkyl and aryl is selected, is different if R 3 is C 1-8 alkanoyl.

Im Rahmen dieser Erfindung bedeutet Alkyl (auch in Wortkombinationen wie Alkoxy oder Carboxyalkyl) C1-10-Alkyl, geradkettig oder verzweigtkettig, vorzugsweise C1-4-Alkyl, während unter einem Arylrest (auch einem der weiter unten genannten Arylreste oder in Wortkombinationen wie Aralkyl) substituiertes oder unsubstituiertes Aryl, insbesondere entsprechendes Phenyl, dessen Substituenten OH, OAlkyl, OAryl, Halogen, Alkyl, Aryl sein können, verstanden wird. Acyl ist im Rahmen dieser Erfindung in erster Linie C1-8-Alkanoyl, C1-8-Alkoxycarbonyl, Aroyl, insbesondere Benzoyl oder substituiertes Benzoyl (worin die Substituenten die gleichen wie bei substituiertem Aryl sind), und gegebenenfalls durch ein oder zwei C1-4-Alkylreste substituiertes Carbamoyl.In the context of this invention alkyl (also in word combinations such as alkoxy or carboxyalkyl) means C 1-10 -alkyl, straight-chain or branched-chain, preferably C 1-4 -alkyl, while under an aryl residue (also one of the aryl residues mentioned below or in word combinations such as Aralkyl) substituted or unsubstituted aryl, in particular corresponding phenyl, the substituents of which can be OH, Oalkyl, OAryl, halogen, alkyl, aryl. In the context of this invention, acyl is primarily C 1-8 alkanoyl, C 1-8 alkoxycarbonyl, aroyl, in particular benzoyl or substituted benzoyl (in which the substituents are the same as in substituted aryl), and optionally by one or two C. 1-4 alkyl radicals substituted carbamoyl.

Entsprechende Reste R1 sind z. B. solche der Formeln -(CR4R5)n -COY oder

Figure 00050001
wobei R4 und R5 = H, Alkyl, Aryl oder substituiertes Aryl, worin die Substituenten aus der OH, OAlkyl, OAryl, Halogen, Alkyl und Aryl umfassenden Gruppe ausgewählt sind, n = 1 - 4, R6 = H, Alkyl, OH, Alkoxy in o-, m- und p-Stellung, COY in o-, m- und p-Stellung, und Y = OR7, wobei R7 = H, Alkyl, Aryl oder substituiertes Aryl wie oben definiert, ein Alkalimetallion ,wie z. B. Na+ oder K+, oder ein Ammoniumion (NH4 + bzw. ein Mono-, Di- oder Trialkylammoniumion oder ein N-Methyl-D-glucammoniumsalz) bedeuten, oder Y = NR8R9, wobei R8 und/oder R9 = H, Alkyl, Aryl oder substituiertes Aryl wie oben definiert oder Aralkyl bedeuten, sein können. Im Falle des Vorliegens asymmetrischer C-Atome sind die entsprechenden D- und L-Formen, Enantiomere und Diastereomere sowie die Racemate bzw. Enantiomeren- und Diasteromerengemische ebenfalls Gegenstand der Erfindung.Corresponding radicals R 1 are z. B. those of the formulas - (CR 4 R 5 ) n -COY or
Figure 00050001
where R 4 and R 5 = H, alkyl, aryl or substituted aryl, where the substituents are selected from the group consisting of OH, Oalkyl, OAryl, halogen, alkyl and aryl, n = 1-4, R 6 = H, alkyl, OH, alkoxy in the o-, m- and p-positions, COY in the o-, m- and p-positions, and Y = OR 7 , where R 7 = H, alkyl, aryl or substituted aryl as defined above, an alkali metal ion , such as B. Na + or K + , or an ammonium ion (NH 4 + or a mono-, di- or trialkylammonium ion or an N-methyl-D-glucammonium salt), or Y = NR 8 R 9 , where R 8 and / or R 9 = H, alkyl, aryl or substituted aryl as defined above or aralkyl. If asymmetric carbon atoms are present, the corresponding D and L forms, enantiomers and diastereomers and also the racemates or mixtures of enantiomers and diasteromers are also a subject of the invention.

In besonders bevorzugten Verbindungen der Formel I steht R1 für Carboxy-C1-4-alkyl oder C1-4-Alkoxycarbonyl-C1-4-alkyl oder für Carboxyphenyl, und R2 und R3 für Wasserstoff, worin die Carboxygruppe in freier Form oder in Salzform vorliegt. Hervorzuheben sind die in den Beispielen genannten Verbindungen der Formel I und ihre Salze. In particularly preferred compounds of the formula I, R 1 is carboxy-C 1-4 -alkyl or C 1-4 alkoxycarbonyl-C 1-4 -alkyl or carboxyphenyl, and R 2 and R 3 are hydrogen, in which the carboxy group in is in free form or in salt form. The compounds of the formula I and their salts mentioned in the examples should be emphasized.

Die erfindungsgemäßen Verbindungen werden z. B. hergestellt, indem Madurahydroxylakton bzw. Maduransäure (3,9,11,14,15-Pentahydroxy-10-methyl-7-methoxy-1,8,13-trioxo-1,3,5,6,8,13-hexahydro-naphthaceno[1,2-f]benzoisofuran) der Formel II

Figure 00070001
mit Hydrazinoalkylcarbonsäuren oder Hydrazinophenylcarbonsäuren bzw. deren Estern und Amiden, gegebenenfalls in Form ihrer Salze, umgesetzt werden. Die Reaktion wird unter Verwendung geeigneter Lösungsmittel, z. B. Eisessig, durchgeführt. Die Reaktionstemperatur liegt gewöhnlich bei der Siedetemperatur des Lösungsmittels, die Reaktionszeit kann bis zu einigen Stunden betragen.The compounds of the invention are, for. B. prepared by madura hydroxylactone or maduranic acid (3,9,11,14,15-pentahydroxy-10-methyl-7-methoxy-1,8,13-trioxo-1,3,5,6,8,13- hexahydro-naphthaceno [1,2-f] benzoisofuran) of the formula II
Figure 00070001
with hydrazinoalkylcarboxylic acids or hydrazinophenylcarboxylic acids or their esters and amides, optionally in the form of their salts. The reaction is carried out using suitable solvents, e.g. B. glacial acetic acid. The reaction temperature is usually the boiling point of the solvent, and the reaction time can be up to a few hours.

Erfindungsgemäß hergestellte Verbindungen der Formel I können in an sich bekannter Weise in andere Verbindungen der Formel I überführt werden. So können erhältliche Verbindungen der Formel I mit Y = O-Alkyl durch alkalische Verseifung, z. B. mit 2M Natronlauge, und anschließendes Ansäuern, z. B. mit 2M Salzsäure, in die entsprechenden Säuren (Formel I mit Y = OH) umgewandelt werden. Andererseits können die erhaltenen Verbindungen der Formel I mit R2 bzw. R3 = H durch Acylierung der phenolischen OH-Gruppen in einem zweiten Schritt in O-Acylderivate, Formel I mit R2 bzw. R3 = H bzw. Acyl (z. B. -CO-Alkyl, -COO-Alkyl) überführt werden. Dieser Reaktionsschritt wird nach üblichen Methoden der Acylierung phenolischer OH-Gruppen, z. B. mittels Säureanhydrid (z. B. Acetanhydrid bzw. Propionsäureanhydrid) oder mittels Chlorameisenester (z. B. Chlorameisensäuremethylester) in alkalischer Lösung, z. B. in 2M Natronlauge oder in Tetrahydrofuran/Triethylamin durchgeführt. Die Reaktionstemperatur kann dabei von -20° C bis +20° C liegen.Compounds of the formula I prepared according to the invention can be converted into other compounds of the formula I in a manner known per se. So available compounds of formula I with Y = O-alkyl by alkaline saponification, for. B. with 2M sodium hydroxide solution, and subsequent acidification, for. B. with 2M hydrochloric acid, can be converted into the corresponding acids (formula I with Y = OH). On the other hand, the compounds of formula I obtained with R 2 or R 3 = H by acylation of the phenolic OH groups in a second step in O-acyl derivatives, formula I with R 2 or R 3 = H or acyl (e.g. B. -CO-alkyl, -COO-alkyl) are transferred. This reaction step is carried out by customary methods of acylating phenolic OH groups, e.g. B. by means of acid anhydride (z. B. Acetic anhydride or propionic anhydride) or by means of chloroformic esters (z. B. Methyl chloroformate) in an alkaline solution, for. B. in 2M sodium hydroxide solution or in tetrahydrofuran / triethylamine. The reaction temperature can be from -20 ° C to + 20 ° C.

Die erhaltenen Verbindungen mit Y = OH können nach üblichen Methoden in entsprechende Salze mit Y = OR7 umgewandelt werden, wobei R7 ein Alkalimetallion (z. B. Na, K) oder ein Ammoniumion (NH4, ein Mono-, Di- oder Trialkylammoniumion, z. B. ein Triethylammoniumion oder ein N-Methyl-D-glucammoniumion) sein kann. Die synthetisierten Verbindungen können mittels üblicher Methoden (z. B. durch Umkristallisation bzw. Säulenchromatographie) gereinigt werden.The compounds obtained with Y = OH can be converted into corresponding salts with Y = OR 7 by customary methods, where R 7 is an alkali metal ion (for example Na, K) or an ammonium ion (NH 4 , a mono-, di- or Trialkylammonium ion, e.g. a triethylammonium ion or an N-methyl-D-glucammonium ion). The synthesized compounds can be purified by means of customary methods (for example by recrystallization or column chromatography).

Die erfindungsgemäß bereitgestellten Verbindungen hemmen das Wachstum von Bakterien, insbesondere von grampositiven Bakterien, speziell von multiresistenten Staphylokokken sowie von Enterokokken. Von besonderer Bedeutung ist, daß die Verbindungen auch gegen chinolonresistente Staphylokokken sowie gegen mehrfachresistente, auch gegen glykopeptidresistente, z. B. gegen vancomycinresistente Hospitalstämme (MRSA) hochwirksam sind.Inhibit the connections provided according to the invention the growth of bacteria, especially gram-positive Bacteria, especially from multi-resistant staphylococci as well as enterococci. Of particular importance is that the compounds are also resistant to quinolones Staphylococci as well as against multi-resistant, also against glycopeptide resistant, e.g. B. against vancomycin resistant Hospital strains (MRSA) are highly effective.

In einem Mikrobouillonverdünnungstest nach DIN 58 940 (Teil 8) wurden die Verbindungen auf ihre minimale Hemmkonzentration (MHK) gegen folgende Bakterienstämme geprüft: Staphylococcus aureus, Stämme 8325-4 (empfindlicher Staphyloccocus aureus-Stamm, repräsentativ für die Species), NCTC 6571 (empfindlicher internationaler Kontrollstamm), 108/83 ("alter" MRSA ohne Chinolonresistenz), 134/94 ("neuer" MRSA, mit Chinolonresistenz), Staph. epidermidis CCM 2124 (empfindlicher Kontrollstamm), Enteroococcus faecium 70/90 (gegen Vancomycin resistenter Stamm) und 64/3 (empfindlicher Stamm) . Zum Vergleich wurden die bekannten, wenn auch strukturell verschiedenen, Substanzen Vancomycin, Teicoplanin und Ciprofloxacin in die Untersuchungen einbezogen.In a microbouillon dilution test according to DIN 58 940 (part 8), the compounds were tested for their minimum inhibitory concentration (MIC) against the following bacterial strains: Staphylococcus aureus , strains 8325-4 (sensitive Staphyloccocus aureus strain, representative of the species), NCTC 6571 (sensitive international control strain), 108/83 ("old" MRSA without quinolone resistance), 134/94 ("new" MRSA, with quinolone resistance ), Staph . epidermidis CCM 2124 (sensitive control strain ), Enteroococcus faecium 70/90 (strain resistant to vancomycin) and 64/3 (sensitive strain). For comparison, the known, albeit structurally different, substances vancomycin, teicoplanin and ciprofloxacin were included in the investigations.

Die Ergebnisse der antibakteriellen Testung sind in der Tabelle zusammengefaßt. Aus den Resultaten geht hervor, daß die erfindungsgemäß dargestellten Substanzen gegen einige Bakterienstämme die Hemmwerte der Vergleichssubstanzen signifikant übertreffen und erfolgreich bakterielle Resistenzen überwinden können.The results of the antibacterial testing are in the Table summarized. The results show that the substances shown according to the invention against some strains of the inhibitors of the comparison substances significantly outperform and successful bacterial Can overcome resistance.

Die Verbindungen der allgemeinen Formel I eignen sich aufgrund ihrer antibakteriellen Eigenschaften zur Anwendung als Arzneimittel bei bakteriellen Infektionen, insbesondere bei Infektionen mit multiresistenten Staphylokokken. Bei solchen Erkrankungen können die Verbindungen der Formel I entweder allein oder mit physiologisch verträglichen Hilfs- oder Trägerstoffen angewandt werden, wobei prinzipiell alle üblichen pharmakologischen Anwendungsformen und physiologisch verträglichen Dosierungen möglich sind. Die Applikation erfolgt z. B. oral oder parenteral, wie z. B. intravenös. The compounds of general formula I are suitable due to their antibacterial properties as a medicine for bacterial infections, in particular in infections with multi-resistant staphylococci. In such diseases, the connections of formula I either alone or with physiologically compatible Auxiliaries or carriers are used, in principle all the usual pharmacological application forms and physiologically acceptable dosages possible are. The application takes place e.g. B. orally or parenterally, such as B. intravenously.

BeispieleExamples Beispiel 1example 1 Substanz 1:Substance 1:

2-(4-Carboxyphenyl)-maduraphthalazin (2-(4-Carboxyphenyl-10,12,15,16-tetrahydroxy-8-methoxy-11-methyl-1,9,14-trioxol,2,6,7,9,14-hexahydro-naphthaceno-[1,2g]-phthalazin-), Formel I mit R1 = 4-Carboxyphenyl, R2 ,R3 = H, C33H22N2O10 (606,54).2- (4-carboxyphenyl) maduraphthalazine (2- (4-carboxyphenyl-10,12,15,16-tetrahydroxy-8-methoxy-11-methyl-1,9,14-trioxole, 2,6,7,9 , 14-hexahydro-naphthaceno [1.2 g] phthalazine), formula I with R 1 = 4-carboxyphenyl, R 2 , R 3 = H, C 33 H 22 N 2 O 10 (606.54).

Eine Mischung von 100 mg (0,2 mmol) Madurahydroxylakton (80-prozentig) und 50 mg 4-Hydrazino-benzoesäure (0,2 mmol) wurde in 10 ml Eisessig 4 Stunden unter Rückfluß gekocht. Die erhaltenen roten Kristalle wurden mit Ether gewaschen.A mixture of 100 mg (0.2 mmol) madura hydroxylactone (80 percent) and 50 mg of 4-hydrazino-benzoic acid (0.2 mmol) was refluxed in 10 ml of glacial acetic acid for 4 hours cooked. The red crystals obtained were used Washed ether.

Die Substanz wurde zweimal über präparative DC (Merck Fertigplatten Si 60, 1 mm, Laufmittel CH2Cl2/CH3OH 9:1) gereinigt, in THF gelöst, filtriert und mit Petrolether ausgefällt. Ausbeute 78 mg (63 % der Theorie), Fp. > 350° C, Reinheit nach HPLC (Eurospher, Acetonitril/Wasser 3:2): 94,7 %, t = 9,4 min, DC (Merck Alufolie Si 60), Laufmittel CH2Cl2/CH3OH 9:1) Rf=0,77, MS FAB (3NBA) [M+H]': m/z = gefunden 607,1,
1H NMR (DMSO-D6): d(ppm)=14,1, 13,6, 12,98, 11,2 (4H,s, 10-,12-,15-,16-OH) 8,6 (1H,s,4-CH) 7,3 und 7,5 (2xlH,s,5-CH und 13-CH), 7,8, 7,83, 8,08, 8,12 (4H, 2-Phenylen), 3,85 (3H, s, 8-OCH,) 2,1 (3H, s, 11-CH3),The substance was purified twice on preparative TLC (Merck Si 60, 1 mm finished plates, CH 2 Cl 2 / CH 3 OH 9: 1 eluent), dissolved in THF, filtered and precipitated with petroleum ether. Yield 78 mg (63% of theory), mp.> 350 ° C, purity according to HPLC (Eurospher, acetonitrile / water 3: 2): 94.7%, t = 9.4 min, TLC (Merck aluminum foil Si 60) , Solvent CH 2 Cl 2 / CH 3 OH 9: 1) R f = 0.77, MS FAB (3NBA) [M + H] ': m / z = found 607.1,
1 H NMR (DMSO-D 6 ): d (ppm) = 14.1, 13.6, 12.98, 11.2 (4H, s, 10-, 12-, 15-, 16-OH) 8, 6 (1H, s, 4-CH) 7.3 and 7.5 (2xlH, s, 5-CH and 13-CH), 7.8, 7.83, 8.08, 8.12 (4H, 2 -Phenylene), 3.85 (3H, s, 8-OCH,) 2.1 (3H, s, 11-CH 3 ),

Beispiel 2Example 2 Substanz 2:Substance 2:

2-Ethoxycarbonylmethyl-maduraphthalazin (10, 12, 15, 16-Tetrahydroxy-8-methoxy-2-ethoxycarbonylmethyl-11-methyl-1,9,14-trioxo-1,2,6,7,9,14-hexahydronaphthacena-[1,2-g]-phthalazin), Formel I mit R1 = CH2COOC2H5, R2, R3 = H, C30H24N2O10 (572,53).2-ethoxycarbonylmethyl-maduraphthalazine (10, 12, 15, 16-tetrahydroxy-8-methoxy-2-ethoxycarbonylmethyl-11-methyl-1,9,14-trioxo-1,2,6,7,9,14-hexahydronaphthacena- [1,2-g] phthalazine), Formula I with R 1 = CH 2 COOC 2 H 5 , R 2 , R 3 = H, C 30 H 24 N 2 O 10 (572.53).

Die Mischung von lg Maduransäure (97-prozentig) (2 mmol) und 400 mg Hydrazinoessigsäureethylester-Hydrochlorid (2,5 mmol) wurde in 20 ml Eisessig unter Rühren 2 Stunden gekocht. Nach Absaugen wurde gut mit Wasser und Eisessig gewaschen und aus Eisessig umkristallisiert. Hellrote Kristalle, Fp. 324 - 25° C (Zersetzung) Ausbeute: 622 mg (54 % der Theorie). Reinheit nach HPLC (Nucleosil RP18, Acetonitril/Wasser 3:2): 98,14 % , t = 10,45 min,
DC (Merck Alufolie Si 60): Butylacetat/Eisessig 4:1: Rf = 0,87,
MS FAB (3NBA) [M+H]': m/z = gefunden 573,1,
1H NMR (DMSO-D6) d(ppm) : 14,07 13,56 12,77 11,18 (4xH,s,10,12,15 und 16-OH) 8,50 (lH,s,4-CH), 7,40 und 7,28 (2H,s,5-CH und 13-CH), 4,97 (2H,s,NCH2) 4,15-4,25 (2H,q, CH2 von Ethyl), 3,81 (3H,s,8-OCH3) 2,08 (3H,s,10-CH3), 1,20 - 1,268 (3H,t,CH3 von Ethyl)The mixture of 1 g of maduranic acid (97 percent) (2 mmol) and 400 mg of hydrazinoacetic acid ethyl ester hydrochloride (2.5 mmol) was boiled in 20 ml of glacial acetic acid with stirring for 2 hours. After suction, the product was washed well with water and glacial acetic acid and recrystallized from glacial acetic acid. Light red crystals, mp. 324 - 25 ° C (decomposition) Yield: 622 mg (54% of theory). Purity according to HPLC (Nucleosil RP18, acetonitrile / water 3: 2): 98.14%, t = 10.45 min,
TLC (Merck aluminum foil Si 60): butyl acetate / glacial acetic acid 4: 1: R f = 0.87,
MS FAB (3NBA) [M + H] ': m / z = found 573.1,
1 H NMR (DMSO-D 6 ) d (ppm): 14.07 13.56 12.77 11.18 (4xH, s, 10.12.15 and 16-OH) 8.50 (1H, s, 4 -CH), 7.40 and 7.28 (2H, s, 5-CH and 13-CH), 4.97 (2H, s, NCH 2 ) 4.15-4.25 (2H, q, CH 2 from ethyl), 3.81 (3H, s, 8-OCH 3 ) 2.08 (3H, s, 10-CH 3 ), 1.20 - 1.268 (3H, t, CH 3 from ethyl)

Beispiel 3Example 3 Substanz 3:Substance 3:

2-Carboxymethyl-maduraphthalazin (10,12,15,16-Tetrahydroxy-8-methoxy-2-carboxymethyl-11-methyl-1,9,14-trioxo-1,2,6,7,9,14-hexahydro-naphthaceno-[1,2-g]-phthalazin), Formel I mit R1 = CH2COOH, R2,R3 = H, C28H20N2O10 (544,47).2-carboxymethyl-maduraphthalazine (10,12,15,16-tetrahydroxy-8-methoxy-2-carboxymethyl-11-methyl-1,9,14-trioxo-1,2,6,7,9,14-hexahydro- naphthaceno [1,2-g] phthalazine), Formula I with R 1 = CH 2 COOH, R 2 , R 3 = H, C 28 H 20 N 2 O 10 (544.47).

570 mg (1 mmol) 2-Carbethoxymethyl-maduraphthalazin (Substanz 2) wurden in 35 ml 2M Natronlauge 1 Tag stehen gelassen. Anschließend wurde mit 2M Salzsäure angesäuert. Die erhaltenen roten Kristalle wurden durch Umkristallisieren oder durch Kochen in Eisessig bzw. durch Lösen in Tetrahydrofuran und Ausfällen mit Petrolether gereinigt. Fp. 234 - 36° C (Zersetzung), Ausbeute: 322 mg (59 % der Theorie).
Reinheit nach HPLC (Nucleosil RP18 , Acetonitril/Wasser 3:2) 99,8 % , t = 0,87 min, DC (Merck Alufolie Si 60): Butylacetat/Eisessig 4:1: Rf= 0,31,
MS FAB (3NBA) [M+H]+: m/z = gefunden 545,0,
1H NMR (CDCl3) d(ppm): 14,0 , 13,5 , 12,8 , 11,2 (4H,s, 10,12,15 und 16-OH) 8,42 (1H,s,4-CH), 7,2 und 7,3 (2H,s,5-CH und 13-CH), 3,9 (3H, s, 7-OCH3) 2,9 und 2,5 (2x2H,s,6-und 7-CH2), 2,1 (3H,s,10-CH3),
13C NMR (CDCl3) 28 C-Atome d(ppm): 187,66 und 185,54 (Chinongruppe), 169,0 (2-COOH), 61,04 (OCH3), 52,30 (NCH2), 29,21 und 22,21 (6- und 7-CH2), 8,17 (11-CH3)
13C NMR DEPT 135: d(ppm): 139,44 (CH=N) 114,19 , 106,06 (2x ArH), 60,79 (8-OCH3), 52,04 (NCH2), 29,05, 21,96 (2x CH2), 7,92 (11-CH3)570 mg (1 mmol) of 2-carbethoxymethyl-maduraphthalazine (substance 2) were left to stand in 35 ml of 2M sodium hydroxide solution for 1 day. The mixture was then acidified with 2M hydrochloric acid. The red crystals obtained were purified by recrystallization or by boiling in glacial acetic acid or by dissolving in tetrahydrofuran and precipitating with petroleum ether. Mp 234-36 ° C (decomposition), yield: 322 mg (59% of theory).
Purity according to HPLC (Nucleosil RP18, acetonitrile / water 3: 2) 99.8%, t = 0.87 min, TLC (Merck aluminum foil Si 60): butyl acetate / glacial acetic acid 4: 1: R f = 0.31,
MS FAB (3NBA) [M + H] + : m / z = found 545.0,
1 H NMR (CDCl 3 ) d (ppm): 14.0, 13.5, 12.8, 11.2 (4H, s, 10.12.15 and 16-OH) 8.42 (1H, s, 4-CH), 7.2 and 7.3 (2H, s, 5-CH and 13-CH), 3.9 (3H, s, 7-OCH 3 ) 2.9 and 2.5 (2x2H, s , 6-and 7-CH 2 ), 2.1 (3H, s, 10-CH 3 ),
13 C NMR (CDCl 3 ) 28 C atoms d (ppm): 187.66 and 185.54 (quinone group), 169.0 (2-COOH), 61.04 (OCH 3 ), 52.30 (NCH 2 ), 29.21 and 22.21 (6- and 7-CH 2 ), 8.17 (11-CH 3 )
13 C NMR DEPT 135: d (ppm): 139.44 (CH = N) 114.19, 106.06 (2x ArH), 60.79 (8-OCH 3 ), 52.04 (NCH 2 ), 29 , 05, 21.96 (2x CH 2 ), 7.92 (11-CH 3 )

Aus der Substanz 3 kann durch Zusatz eines Amins, beispielsweise Triethylamin oder N-Methyl-D-glucamin, in einem geeigneten Lösungsmittel, beispielsweise Tetrahydrofuran, ein wasserlösliches Trialkylammoniumsalz, beispielsweise ein Triethylammoniumsalz oder ein N-Methyl-D-glucammoniumsalz, gewonnen werden.Substance 3 can be added, for example, by adding an amine Triethylamine or N-methyl-D-glucamine, all in one suitable solvents, for example tetrahydrofuran, a water soluble trialkylammonium salt, for example a triethylammonium salt or an N-methyl-D-glucammonium salt, be won.

Beispiel 4Example 4 Substanz 4:Substance 4:

2-(D,L-a-Carboxypropyl)-maduraphthalazin (10,12,15,16-Tetrahydroxy-8-methoxy-2-(D,L-a-carboxypropyl-11-methyl-1,9,14-trioxo-1,2,6,7,9,14-hexahydronaphthaceno-[1,2-g]-phthalazin), Formel I mit R1.= D,L-a-Carboxy-propyl, R2 ,R3 = H, C30H24N2O10 (572,15). 2- (D, La-carboxypropyl) maduraphthalazine (10,12,15,16-tetrahydroxy-8-methoxy-2- (D, La-carboxypropyl-11-methyl-1,9,14-trioxo-1,2 , 6,7,9,14-hexahydronaphthaceno [1,2-g] phthalazine), formula I with R 1. = D, La-carboxypropyl, R 2 , R 3 = H, C 30 H 24 N 2 O 10 (572.15).

Die Mischung von 2 g (4,1 mmol) Madurahydroxylakton und 0,52 g (4,4 mmol) D,L-a-Hydrazinobuttersäure wurde in 50 ml Eisessig 2 Stunden unter Rückfluß gekocht. Die erhaltenen dunkelroten Kristalle wurden nach Stehen über Nacht abgesaugt, mit Ether gewaschen und aus Eisessig umkristallisiert. Ausbeute 1,8 g (76 % der Theorie), Fp. 225 - 30° C (Zersetzung),
Reinheit nach HPLC (RP18 Eurospher 100 C7 , Acetonitril/Wasser 3:2 + 0,05-prozentige Trifluoressigsäure): 99,6 %, t = 13,3 min,
DC (Merck Alufolie Si 60): Butylacetat/Eisessig 4:1: Rf= 0,79,
MS FAB (3NBA) [M+H]+: m/z = gefunden 573,4,
1H NMR (DMSO-D6) d(ppm): 14,1 , 13,6 , 12,9 , 11,3 (4H,s, 10,12,15 und 16-OH)
8,5 (1H,s,4-CH), 7,2 und 7,4 (2H,s,5-CH und 13-CH), 5,3 (1H,d,NCH), 3,9 (3H,s,7-OCH3), 2,0 (3H,s,10CH3), 0,9 (3H,s, CH3 aliph.).
13C NMR (DMSO-D6) Dept 135: d(ppm): 29,48, 22,43, 22,22 (3 x CH2).The mixture of 2 g (4.1 mmol) of madura hydroxylactone and 0.52 g (4.4 mmol) of D, La-hydrazinobutyric acid was boiled under reflux in 50 ml of glacial acetic acid for 2 hours. The dark red crystals obtained were suction filtered after standing overnight, washed with ether and recrystallized from glacial acetic acid. Yield 1.8 g (76% of theory), mp. 225-30 ° C. (decomposition),
Purity according to HPLC (RP18 Eurospher 100 C7, acetonitrile / water 3: 2 + 0.05% trifluoroacetic acid): 99.6%, t = 13.3 min,
TLC (Merck aluminum foil Si 60): butyl acetate / glacial acetic acid 4: 1: R f = 0.79,
MS FAB (3NBA) [M + H] + : m / z = found 573.4,
1 H NMR (DMSO-D6) d (ppm): 14.1, 13.6, 12.9, 11.3 (4H, s, 10, 12, 15 and 16-OH)
8.5 (1H, s, 4-CH), 7.2 and 7.4 (2H, s, 5-CH and 13-CH), 5.3 (1H, d, NCH), 3.9 (3H , s, 7-OCH 3 ), 2.0 (3H, s, 10CH 3 ), 0.9 (3H, s, CH 3 aliph.).
13 C NMR (DMSO-D6) Dept 135: d (ppm): 29.48, 22.43, 22.22 (3 x CH 2 ).

In den Beispielen bedeuten:

DC
- Dünnschichtchromatographie
THF
- Tetrahydrofuran
HPLC
- High Performance Liquid Chromatography
min
- Minute
Fp.
- Schmelzpunkt
MS
- Massenspektrometrie
NMR
- Nuclear Magnetic Resonance
Figure 00140001
In the examples:
DC
- thin layer chromatography
THF
- tetrahydrofuran
HPLC
- High performance liquid chromatography
min
- minute
Mp.
- melting point
MS
- mass spectrometry
NMR
- Nuclear Magnetic Resonance
Figure 00140001

Claims (8)

  1. Polycyclic phthalazine derivatives of the general formula I
    Figure 00170001
    wherein R1 represents carboxyalkyl or carboxyaryl and R2 and R3 each independently of the other represents hydrogen or acyl, and salts, esters and amides of compounds of formula I, with the proviso that, when R3 represents C1-8-alkanoyl, R1 is other than optionally substituted carboxyphenyl, wherein the substituents are selected from the group consisting of OH, O-alkyl, O-aryl, halogen, alkyl and aryl.
  2. Compounds of formula I according to claim 1, wherein R1 represents a radical of the formula -(CR4R5)n-COY or
    Figure 00170002
    wherein R4 and R5 represent H, alkyl or aryl or substituted aryl, wherein the substituents are selected from the group consisting of OH, O-alkyl, O-aryl, halogen, alkyl and aryl, n is from 1 to 4, R6 represents H, alkyl, OH, alkoxy, and Y represents OR7, wherein R7 is H, alkyl, aryl or substituted aryl as defined above, an alkali metal ion or an ammonium ion, or Y represents NR8R9 wherein R8 and R9 each independently of the other represents H, alkyl, aryl or substituted aryl as defined above, or aralkyl.
  3. Compounds of formula I according to claim 1, wherein R1 represents carboxy-C1-4-alkyl or C1-4-alkoxycarbonyl-C1-4-alkyl or carboxyphenyl, and R2 and R3 are hydrogen, the carboxy group being in free form or in salt form.
  4. Compounds of formula I according to claim 1 in salt form.
  5. Compounds of formula I according to claim 2, wherein R7 represents a trialkylammonium ion or an N-methyl-D-glucammonium ion.
  6. 2-Carboxymethyl-maduraphthalazine and salts thereof according to claim 1.
  7. Use of compounds of formula I according to any one of claims 1 to 6 in the preparation of medicaments.
  8. Medicament containing a compound of formula I according to any one of claims 1 to 6 together with one or more pharmaceutical carriers.
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US4859598A (en) * 1984-03-26 1989-08-22 American Cyanamid Company Antibiotic LL-D42067β
EP0156193B1 (en) * 1984-03-26 1990-12-27 American Cyanamid Company Compounds and compositions for treating protozoal infections with a novel antibiotic

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SK19299A3 (en) 1999-08-06
IL127752A (en) 2003-10-31
AU728361B2 (en) 2001-01-11
DE19719522A1 (en) 1998-02-19
CZ53299A3 (en) 1999-05-12
NO990483L (en) 1999-02-02
JP2000516236A (en) 2000-12-05
KR20000068099A (en) 2000-11-25
GR3036531T3 (en) 2001-12-31
RU2181361C2 (en) 2002-04-20
HUP0001832A3 (en) 2001-07-30
SI0925284T1 (en) 2001-10-31
DK0925284T3 (en) 2001-09-24
PL331610A1 (en) 1999-08-02
CN1228085A (en) 1999-09-08
WO1998007706A1 (en) 1998-02-26
IL127752A0 (en) 1999-10-28
DE59703968D1 (en) 2001-08-09
US6124290A (en) 2000-09-26
ES2160966T3 (en) 2001-11-16
AU3542997A (en) 1998-03-06
CA2261756A1 (en) 1998-02-26
BR9714633A (en) 2000-10-03
HK1019750A1 (en) 2000-02-25
NO990483D0 (en) 1999-02-02
PT925284E (en) 2001-10-30
UA49031C2 (en) 2002-09-16
HUP0001832A2 (en) 2001-05-28
NO312029B1 (en) 2002-03-04
EP0925284A1 (en) 1999-06-30
CN1099417C (en) 2003-01-22
NZ334538A (en) 1999-08-30
ATE202773T1 (en) 2001-07-15

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